The invention relates to the nucleotide analog 9-[2-[[bis[(pivaloyloxy)methoxy]phosphinyl]methoxy]ethyl]adenine (xe2x80x9cadefovir dipivoxilxe2x80x9d or xe2x80x9cADxe2x80x9d) and to its use. The present invention also relates to methods to synthesize AD.
AD is the bis-pivaloyloxymethyl ester of the parent compound 9-[2-(phosphonomethoxy)ethyl]adenine (xe2x80x9cPMEAxe2x80x9d), which has antiviral activity in animals and in humans. AD and PMEA have been described, e.g., U.S. Pat. Nos. 4,724,233 and 4,808,716, EP 481 214, Benzaria et al., Nucleosides and Nucleotides (1995) 14(3-5):563-565, Holy et al., Collect. Czech. Chem. Commun. (1989) 54:2190-2201, Holy et al., Collect. Czech. Chem. Commun. (1987) 52:2801-2809, Rosenberg et al., Collect. Czech. Chem. Commun. (1988) 53:2753-2777, Starrett et al., Antiviral Res. (1992) 19:267-273; Starrett et al., J. Med. Chem. (1994) 37:1857-1864. Heretofore, AD has been provided only as a noncrystalline or amorphous form. It has not been reported to have been prepared as a crystalline material.
Methods for crystallizing organic compounds per se are described in J. A. Landgrebe, Theory and Practice in the Organic Laboratory, 2nd edition, 1977, D.C. Heath and Co., Lexington, Mass., p. 43-51; A. S. Myerson, Handbook of Industrial Crystallization, 1993, Butterworth-Heinemann, Stoneham, Mass., p. 1-101).
The invention provides one or more compositions or methods that meet one or more of the following objects.
A principal object of the invention is to provide compositions comprising novel AD forms having desirable properties for large scale synthesis or for formulation into therapeutic dosages.
Another object is to provide AD having good melting point, and/or flow or bulk density properties, which facilitates manufacturing and formulation of compositions containing AD.
Another object is to provide storage-stable forms of AD.
Another object is to provide AD which can be readily filtered and easily dried.
Another object is to provide highly purified AD having at least about 97% (w/w) purity and preferably at least about 98%.
Another object is to eliminate or minimize by-products made during AD synthesis.
Another object is to provide a method for purifying AD that avoids expensive and time-consuming column chromatography.
The invention accomplishes its primary objects by providing crystalline AD, in particular, an anhydrous crystalline form (hereafter xe2x80x9cForm 1xe2x80x9d), a hydrated form, C20H32N5O8P1.2H2O, (hereafter xe2x80x9cForm 2xe2x80x9d), a methanol solvate form, C20H32N5O8P1.CH3OH, (hereafter xe2x80x9cForm 3xe2x80x9d), a fumaric acid salt or complex, C20H32N5O8P1.C4H4O4 (hereafter xe2x80x9cForm 4xe2x80x9d), a hemisulfate salt or complex, a hydrobromide salt or complex, a hydrochloride salt or complex, a nitrate salt or complex, a mesylate (CH3SO3H) salt or complex, an ethyl sulfonate salt (C2H5SO3H) or complex, a xcex2-naphthylene sulfonic acid salt or complex, an xcex1-naphthylene sulfonic acid salt or complex, an (S)-camphor sulfonic acid salt or complex, a succinic acid salt or complex, a maleic acid salt or complex, an ascorbic acid salt or complex and a nicotinic acid salt or complex.
Invention embodiments include (1) crystalline Form 1 AD essentially having an X-ray powder diffraction (xe2x80x9cXRDxe2x80x9d) spectrum using Cuxe2x80x94Kxcex1 radiation, expressed in degrees 2xcex8 at any one or more (in any combination) of about 6.9, about 11.8, about 12.7, about 15.7, about 17.2, about 20.7, about 21.5, about 22.5, and about 23.3; (2) crystalline Form 2 AD essentially having an XRD spectrum using Cuxe2x80x94Kxcex1radiation, expressed in degrees 2xcex8 at any one or more (in any combination) of about 8.7-8.9, about 9.6, about 16.3, about 18.3, about 18.9, about 19.7, about 21.0, about 21.4, about 22.0, about 24.3, about 27.9, about, 30.8, and about 32.8; (3) crystalline Form 3 AD essentially having an XRD spectrum using Cuxe2x80x94Kxcex1 radiation, expressed in degrees 2xcex8 at any one or more (in any combination) of about 8.1, about 8.7, about 14.1, about 16.5, about 17.0, about 19.4, about 21.1, about 22.6, about 23.4, about 24.2, about 25.4, and about 30.9; and crystalline Form 4 AD essentially having an XRD spectrum using Cuxe2x80x94Kxcex1 radiation, expressed in degrees 2xcex8 at any one or more (in any combination) of about 9.8, about 15.2, about 15.7, about 18.1, about 18.3, about 21.0, about 26.3 and about 31.7.
Invention embodiments include AD crystals having the crystal morphologies shown in any one or more of FIGS. 4-10.
In other embodiments, the invention provides methods to produce AD crystals by allowing crystals to form from a crystallization solution comprising about 6-45% AD and about 55-94% crystallization solvent wherein the crystallization solvent is selected from the group consisting of (1) a mixture between about 1:10 v/v to about 1:3 v/v of acetone:di-n-butyl ether, (2) a mixture between about 1:10 v/v to about 1:3 v/v of ethyl acetate:di-n-propyl ether, (3) a mixture between about 1:10 v/v to about 10:1 v/v of t-butanol:di-n-butyl ether, (4) a mixture between about 1:10 v/v to about 1:3 v/v of methylene chloride:di-n-butyl ether, (5) a mixture between about 1:10 v/v to about 10:1 v/v of diethyl ether:di-n-propyl ether, (6) a mixture between about 1:10 v/v to about 1:3 v/v of tetrahydrofuran:di-n-butyl ether, (7) a mixture between about 1:10 v/v to about 1:3 v/v of ethyl acetate:di-n-butyl ether, (8) a mixture between about 1:10 v/v to about 1:3 v/v of tetrahydropyran:di-n-butyl ether, (9) a mixture between about 1:10 v/v to about 1:3 v/v of ethyl acetate:diethyl ether, (10) t-butyl-methyl ether, (11) diethyl ether, (12) di-n-butyl ether, (13) t-butanol, (14) toluene, (15) isopropyl acetate, (16) ethyl acetate, (17) a mixture consisting essentially of (A) a first crystallization solvent consisting of a first dialkyl ether of the formula R1xe2x80x94Oxe2x80x94R2 wherein R1 is an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, R2 is an alkyl group having 2, 3, 4, 5 or 6 carbon atoms or both R1 and R2 are linked together to form a 5-, 6-, 7-, or 8-membered ring, provided that the dialkyl ether is not methyl-ethyl ether, and (B) a second crystallization solvent selected from the group consisting of (a) a second dialkyl ether of the formula R1xe2x80x94Oxe2x80x94R2, wherein the second dialkyl ether is different from the first dialkyl ether, but is not methyl ethyl ether, (b) toluene, (c) tetrahydrofuran, (d) t-butanol, (e) ethyl acetate, (f) methylene chloride, (g) propyl acetate and (h) isopropanol.
Invention embodiments include purified crystalline AD (e.g., form 1 and/or form 2). Invention embodiments also include compositions comprising crystalline AD (e.g., form 1 and/or form 2) and one or more compounds, such as pharmaceutical excipients or compounds present in reaction mixtures that contain the crystalline AD.
Invention embodiments include a method to produce AD crystals comprising dissolving AD in methanol and allowing crystals to form.
Another embodiment is crystalline AD suitable for pharmaceutical compositions or uses comprising, e.g., one or more of Form 1, Form 2, Form 3 and/or Form 4 AD and a pharmaceutically acceptable carrier(s) for treating viral conditions for which PMEA is known to be active, such as a retroviral infection (HIV, SIV, FIV) or hepatitis B virus or other hepadnavirus infections, or DNA virus infection (human cytomegalovirus or herpesvirus, e.g., HSV1 or HSV2) in humans or animals.
The invention provides a method to produce crystalline Form 2 AD comprising forming AD crystals in the presence of water.
In another embodiment, a method for preparing AD comprises contacting PMEA with chloromethyl pivalate in N-methylpyrrolidinone (NMP, 1-methyl-2-pyrrolidinone) and a trialkylamine such as triethylamine (TEA) and recovering AD.
In a further embodiment, a PMEA composition containing less than about 2% salt is provided, which may be used in a method comprising contacting PMEA containing less than about 2% salt.
In a further embodiment, an AD product is obtained by a process comprising preparing wet granules from a mixture comprising a liquid, Form 1 adefovir dipivoxil and an acceptable excipient and, optionally drying the wet granules.